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Systemic scleroderma involves fibrosis of the skin and
internal organs, but its etiology is poorly understood and it has no known
genetic causes-factors that have hampered the development of models and, in
turn, therapies.

Now,
a North American team has shown that mice harboring a mutant form of the
glycoprotein fibrillin
1 (Fbn1) recapitulated skin fibrosis and
other symptoms seen in patients with systemic scleroderma.1 Although the team showed the therapeutic effect of targeting
different proteins whose expression was altered by the mutant glycoprotein,
future studies will have to zero in on the best target for treating scleroderma
in patients.

FBN1,
a glycoprotein secreted by fibroblasts into the extracellular matrix, is an
essential component of the microfibrils found in many types of connective
tissue. FBN1 also interacts with integrins expressed on other cell types, such
as dermal-infiltrating dendritic cells (DCs), to regulate adhesion.

FBN1
mutations can cause a number of different conditions and diseases that affect
connective tissue, most notably Marfan syndrome.2

In
2006, a team at The Johns Hopkins University led by Harry Dietz
showed that some FBN1 mutations could upregulate signaling by transforming growth factor-b (TGFB; TGFb)-a family of
cytokines that is involved in the proliferation and differentiation of most
cells-to cause aortic aneurysms that occur in some patients with Marfan
syndrome.3

Dietz's
team also identified a few patients harboring FBN1 mutations who
exhibited symptoms of both Marfan syndrome and stiff skin syndrome, a rare
inherited form of skin fibrosis with only about 40 cases reported in the
literature. Subsequently, another Dietz-led team determined that stiff skin
syndrome was caused by mutations in the integrin-binding domain of FBN1
and involved upregulation of TGFb signaling.4

Now,
his newest team has hypothesized that mice with loss-of-function mutations in
the integrin-binding domain of Fbn1 might provide insights into the pathobiology
of another fibrotic disease associated with increased TGFb signaling-scleroderma.5

Indeed,
the team found that the Fbn1-mutant mice exhibited skin fibrosis, high
levels of collagen in the skin and the high levels of anti-nuclear and anti-topoisomerase I (Top1) antibodies in circulation seen in
patients with systemic scleroderma.

Plasmacytoid
DCs isolated from the dermis of the mutant mice and fibroblasts from patients
with systemic scleroderma had high surface levels of integrin b1
(CD29) and activated integrin b3 (GPIIIa; CD61).

In
the Fbn1-mutant mice, a mouse Cd29-activating antibody-which mimicked
Fbn1's interactions with Cd29-decreased skin fibrosis and levels of circulating
anti-nuclear and anti-Top1 antibodies compared with an inactive murine control
antibody.

Knockout
of Cd61 or a pan-specific, anti-Tgfb antibody also
decreased skin fibrosis in the mice compared with normal Cd61 expression
or a control antibody.

In
the patient fibroblasts, a CD29-activating antibody, an anti-CD61 antibody or a
small molecule against type I TGFb receptor decreased
collagen expression compared with inactive control antibodies.

Collectively,
the findings suggest that stiff skin syndrome and systemic scleroderma involve
similar pathological mechanisms (see"Restoring dermal integrity") and thus could potentially be treated with the same
therapeutic strategies, the team wrote in its report in Nature.

There
are no drugs approved to treat stiff skin syndrome or the underlying causes of
systemic scleroderma. Therapies for the latter primarily involve topical or
systemic immunosuppressive drugs to ameliorate symptoms.

Although
stiff skin syndrome and scleroderma have differing or unknown causes, "Dietz
has shown that, once initiated, the diseases appear to have similar biological
processes that converge on the same pathways," Luke Evnin, chairman of the
Scleroderma Research Foundation, told SciBX.
"These mouse models could help us study the biology behind scleroderma and
identify therapeutic strategies for preventing or reversing skin fibrosis."

Evnin,
who is a managing director at life sciences VC MPM Capital, said that the Scleroderma Research
Foundation recruited Dietz about six years ago to work on scleroderma and
funded the research in the Nature study.

"Among
the obstacles to understanding scleroderma are the heterogeneity of the disease-systemic
sclerosis that affects multiple organs-and the variability of its clinical
course. The Nature study helps reduce this complexity by focusing on a
genetic model involving only pathological fibrosis of the skin," said Gary
Nabel, CSO of Sanofi.

Thus,
this high-fidelity model of skin scleroderma could be used to screen for new
compounds to treat the disease or possibly repurpose those in development for
other diseases, he said.

Further work is needed before deciding which
therapeutic strategy-targeting CD29, CD61 or TGFb-has the best chance
in scleroderma.

"A
large body of evidence points to a role of TGFb in scleroderma, and
Dietz's team's work further supports this," said
Thomas Hultsch, senior medical director of translational medicine at Sanofi's Genzyme Corp. unit. "Unraveling the mechanisms that
control TGFb activation in the microenvironment of the dermis will
be central for further development" of the team's findings.

Added
Nabel, "Our reading is that Dietz suggests the integrin pathways may allow
modulation of TGFb in a more controlled way, spatially and
temporally, than targeting the cytokine directly. However, this claim remains
preliminary at the present time."

Evnin
agreed and said that targeting integrins b1 or b3 would probably be a
better strategy than inhibiting TGFb "because the
cytokine is involved in many biological processes and thus is not a good target
for a chronic disease like scleroderma."

He
added, "An obvious next step would be to compare the relative efficacy and
safety of the integrin b3-blocking and integrin b1-activating
approaches in the Fbn1-mutant mouse models."

Hultsch
said that it also would be interesting to dissect the role of the specific TGFb isoforms TGFb1 (TGFB1), TGFb2 (TGFB2) and TGFb3 (TGFB3) in skin fibrosis
using isoform-specific antibodies, inhibitors or knockout models.

Evnin said that one drawback of the Fbn1-mutant
models is that they do not exhibit the potentially life-threatening internal
organ fibrosis seen in patients with systemic scleroderma. "That does
leave open to question whether targeting integrins or TGFb would also prevent or reverse that
fibrosis. While this question can't be answered in mice, our hope is that the
therapeutic effect would indeed be the same," he said.

Dietz did not respond to queries about his team's
follow-on studies in the Fbn1 models.

This
week, Biogen Idec Inc. and the BioFocus subsidiary of Galapagos N.V. announced a three-year collaboration
to identify and validate new targets in scleroderma. Under the terms of the
deal, BioFocus will use its technology platform and human skin models to
deliver new assays and previously unknown, validated targets to Biogen Idec.
Galapagos said that the deal could net BioFocus up to $31 million. Other terms
were not disclosed.

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